Abstract
The increased awareness of obstructive sleep apnoea’s (OSA) links to Alzheimer’s disease and major psychiatric disorders has recently directed an intensified search for their potential shared mechanisms. We hypothesised that neuroinflammation and the microglial TLR2-system may act as a core process at the intersection of their pathophysiology. Moreover, we postulated that inflammatory-response might underlie development of key behavioural and neurostructural changes in OSA. Henceforth, we set out to investigate effects of 3 weeks’ exposure to chronic intermittent hypoxia in mice with or without functional TRL2 (TLR2+/+, C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj;TLR2−/−,C57BL/6-Tlr2tm1Kir). By utilising multimodal imaging in this established model of OSA, a discernible neuroinflammatory response was demonstrated for the first time. The septal nuclei and forebrain were shown as the initial key seed-sites of the inflammatory cascade that led to wider structural changes in the associated neurocircuitry. Finally, the modulatory role for the functional TLR2-system was suggested in aetiology of depressive, anxious and anorexiolytic symptoms in OSA.
Highlights
The increased awareness of obstructive sleep apnoea’s (OSA) links to Alzheimer’s disease and major psychiatric disorders has recently directed an intensified search for their potential shared mechanisms
Previous studies have shown that Toll-like receptors 2 (TLR2) regulates the hypoxic/ischaemic brain damage caused by stroke[4,20,21]
Whilst it has been accepted that OSA promotes a low-grade chronic systemic inflammation[29], it has been a matter of some significant speculation whether it may cause neuroinflammation[2]
Summary
The increased awareness of obstructive sleep apnoea’s (OSA) links to Alzheimer’s disease and major psychiatric disorders has recently directed an intensified search for their potential shared mechanisms. Our group has long hypothesized that inflammatory response might arise during sleep in patients with OSA due to obstructive apnoeic events and associated intermittent hypoxia and a rousals[16]. In order to put this concept to test, we set out to investigate the effects of 3 weeks’ exposure to chronic intermittent hypoxia (IH) in an established mouse model of OSA18,19. This model has been shown to verifiably mimic the electroencephalographic arousals and significant hypoxaemia experienced by patients with OSA. The imaging was complemented by functional tests (weight monitoring, Y-maze, open-field and tail-suspension behavioural tests), imaging versus mRNA expression analysis, and ex vivo analyses of variety of cellular markers
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